Case Presentation: 50-year-old female with HTN and hyperlipidemia was brought to the ED after being found unconscious for an unknown duration. She was last seen well 12-hours prior to presentation. On exam, she was disoriented and somnolent but arousable to repeated stimulation. Vital signs were remarkable for tachycardia (P = 120 bpm) and hypertension (BP = 150/90 mmHg). On exam, she had pinpoint pupils. Cardiopulmonary exam was notable for the tachycardia, but was otherwise reassuring. She had intermittent, spontaneous myoclonus, but reflexes were 2+ and symmetrical. No focal neurologic deficit was noted. Pertinent labs: WBC = 14.6×10^9/L; Na = 148 mmol/L; CK = 425 IU/L. Drug screen was negative; alcohol and salicylate levels were negligible; U/A was normal. CT of the head/neck found no acute abnormality. While in the ED, she became more alert, but significantly more agitated and combative. She was given lorazepam and ziprasidone with good effects. LP, MRI, and EEG were unremarkable. Twelve hours later, she became more oriented and provided additional history. She had self-medicated her insomnia and anxiety with tramadol, which she purchased online for 20 years. For the last 3 years, she reportedly took 25-30 tablets (up to 1500 mg) daily. She noted that her recent purchase was from a new supplier. Twenty-four hours into the admission, she developed nausea, abdominal pain, body aches, anxiety and tremulousness. She was tachycardic and hypertensive. She was started on methadone, clonidine, ketorolac, and clorazepate for opioid withdrawal. At 36 hours, the patient had worsening anxiety and tremulousness. At 48 hours, she was more hyperactive, hyperverbal, and emotionally labile. She complained of a headache but denied abdominal pain, nausea, vomiting, shortness of breath, sweating, fever, or hallucinations. She was then transitioned to fluoxetine and clorazepate, which significantly improved her symptoms. She continued on that regimen at discharge with instructions to taper the clorazepate over a week; her symptoms remained well-controlled at her 2-week outpatient follow-up.

Discussion: Tramadol is an opioid analgesic that, in addition to its action on µ receptors, inhibits serotonin and norepinephrine reuptake. In addition to opiate-withdrawal symptoms, tramadol withdrawal can cause atypical symptoms, including anxiety, paranoia, depersonalization, derealization, visual or auditory hallucinations, numbness or tingling, and tinnitus. Atypical symptoms are seen in approximately one out of eight cases and in persons taking > 400 mg tramadol/day. Tramadol is also available without restriction in many countries leading to widespread use and hence potential for abuse and dependence. There are various reports of tramadol withdrawal in the literature. However, no evidence-based treatment guideline exists. Most case reports included a regimen of clonidine, benzodiazepines, and analgesics for opioid withdrawal component of the tramadol withdrawal syndrome.

Conclusions: Tramadol withdrawal can be complicated to manage due to its combination of opioid receptor agonist and serotonin reuptake inhibitor activities. Awareness of atypical withdrawal symptoms is essential for early diagnosis and treatment. This case demonstrates the potential of SSRIs as an adjuvant in the management of atypical tramadol withdrawal.